□ CASE REPORT □Recurrence of Psoriasis Vulgaris Accompanied by Treatment
with C-C Chemokine Receptor Type 4 (CCR4) Antibody(Mogamulizumab) Therapies in a Patient with Adult
T cell Leukemia/ Lymphoma: Insight into
Autoinflammatory Diseases
Kazuho Morichika 1, Takeaki Tomoyose 1, Taeko Hanashiro 1, Natsuki Shimabukuro 1,
Keita Tamaki 1, Iori Tedokon 1, Yukiko Nishi 1, Sawako Nakachi 1, Ken-nosuke Karube 2,
Takuya Fukushima 3, Takeharu Katoh 4, Koichi Ohshima 4 and Hiroaki Masuzaki 1

Abstract
Adult T cell leukemia / lymphoma (ATL) is one of the most aggressive hematological malignancies causedby human T-lymphotropic virus type-I (HTLV-1). Mogamulizumab is a new defucosylated humanized monoclonal antibody agent which targets C-C chemokine receptor type 4 (CCR4) expressed occasionally on thesurface of ATL cells. However, adverse events such as drug eruptions have also been highlighted, at least inpart, via the dysfunction of regulatory T cells (Tregs). We herein report a pronounced recurrence of systemic
psoriasis vulgaris accompanied by the treatment of mogamulizumab in a patient with ATL. Pathological examinations may suggest a mechanistic link between the recurrence of autoinflammatory diseases and antiCCR4 antibody therapies.
Key words: adult T cell leukemia / lymphoma (ATL), C-C chemokine receptor type 4 (CCR4), regulatory T
cell (Treg), psoriasis vulgaris, autoinflammatory disease(Intern Med 55: 1345-1349, 2016)(DOI: 10.2169/internalmedicine.55.5997)

Introduction
Among a variety of hematological malignancies, the prognosis is extremely poor in patients with adult T cell leukemia/ lymphoma (ATL) (1, 2). Some previous reports havesuggested that the origin of ATL may be regulatory T cells(Tregs) (3). Recently, a new antibody agent, mogamulizumab, which binds specifically to chemokine receptor type 4(CCR4), was launched for the treatment of intractable
ATL (4). The drug exerts outstanding anti-ATL effects
through the regulation of antibody-dependent cellular cyto-

toxicity (ADCC) activities (5). However, adverse events
such as drug eruptions and Stevens-Johnson syndrome havealso been reported, presumably via the profound reductionof Tregs (6). In this context, we herein report a rare case of
drastic recurrence of systemic psoriasis vulgaris via the administration of mogamulizumab in a patient with ATL (unfavorable chronic subtype).
Autoinflammatory diseases are non-autoimmune disordersof inappropriate inflammation provoked by autostimulatory
mechanisms through a variety of extracellular or intrinsic
signaling molecules (7). In particular, psoriasis vulgaris iscaused, at least in part, by the autostimulation of mast

１

Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate Schoolof Medicine, University of the Ryukyus, Japan, ２Department of Cell Biology and Pathology, Graduate School of Medicine, University of the
Ryukyus, Japan, ３Laboratory of Immunohematology, School of Health Sciences, Faculty of Medicine, University of the Ryukyus, Japan and４
Department of Pathology, Kurume University School of Medicine, Japan
Received for publication June 18, 2015; Accepted for publication September 15, 2015
Correspondence to Dr. Hiroaki Masuzaki, hiroaki@med.u-ryukyu.ac.jp1345

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Figure 1. Macroscopic and microscopic findings in the skin of the patient. a-c) Newly occurring
nodular erythemas (15-60 mm in diameter) after mogamulizumab administration. The plaques were
erythematous with sharply-defined margins and hyperkeratosis. d) The pathological examination of
the nodular erythemas (Hematoxylin and Eosin staining 200×) revealed Munro’s microabscess (empty arrow-head), infiltration of lymphocytes into the superficial dermis (circled by black arrow-heads),
and elongation of rete ridges (empty arrows), hyperkeratosis, all of which were compatible with thefindings of psoriasis vulgaris.

cells (8), in which a lower activity of Tregs is considerably
involved in its pathophysiology. Indeed, the present casedemonstrated a substantial reduction of functional Tregs in
the skin during a recurrence of psoriasis vulgaris after
mogamulizumab administration. Therefore, the present caseled us to hypothesize that a mogamulizumab-induced excessive reduction of functional Tregs may aggravate a variety
of autoinflammatory diseases.

Case Report
A 46-year-old female visited our hospital complaining ofsystemic lymphadenopathy and general malaise. She had
been a healthy carrier of human T-lymphotropic virus-I(HTLV-1). In the peripheral blood, the white blood cellcount was 85,000/μL (neutrophils 6%, lymphocytes 32%,
monocytes 2%, and abnormal lymphocytes 60%), hemoglobin was 8.2 g/dL and platelet count was 32.8×104/μL. By
flow cytometry analyses of the peripheral blood, we detected ATL cells with CD4+, CD8-, CD25+, thereby diagnosing her with ATL (unfavorable chronic type with elevatedlactate dehydrogenase). Unfortunately, standard chemotherapy did not improve her lymphadenopathy. Despite subsequent salvage chemotherapy, ATL cells in the peripheral

blood remained. Because a CCR4 test (9) was positive, we
administered 5 courses of mogamulizumab therapy (4).
Surprisingly, systemic nodular erythemas emerged at theend of the fifth course of mogamulizumab therapy. Initially,
we considered such erythemas to be mogamulizumabinduced dermatitis, thus we discontinued mogamulizumab
administration. A dermatological inspection revealed that theerythemas were characterized by a distinct border from adjacent normal skin, accompanied by apparent hyperkeratosis(Fig. 1a-c). A pathological examination demonstrated parakeratosis in the surface epidermis, Munro‘s abscess and theinfiltration of inflammatory cells (Fig. 1d). These findings
were consistent with those of psoriasis vulgaris. The entire
clinical course of her psoriasis vulgaris was approximately
20 years, with several cycles of remission and aggravation.
In sharp contrast to the present systemic erythema, extensionof the skin lesion in a previous episode of psoriasis vulgaris
was localized only in the occipital area. Eventually, the current recurrence of psoriasis vulgaris was improved by beclomethasone ointment and phototherapy within 2 weeks.
Both functional Tregs and ATL cells are known to bepositive for CD4, CCR4 and FoxP3 (4, 9-13). Therefore, we
distinguished functional Tregs from ATL cells by the presence of atypical nuclei. In immunohistochemical analyses

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performed during recurrence of psoriasis vulgaris, the number of FoxP3-positive lymphocytes without atypical nuclei,
which corresponded to normal Tregs, was 13 lymphocytes
per 10 high power fields (HPF) (1.3 cell counts / HPF+-1.4). In contrast, these lymphocytes were substantially increased to 39 lymphocytes per 7 HPF (5.6 cell counts / HPF+-6.5) when psoriasis vulgaris was much improved(Fig. 2a-1, a-2 and c-1). Similarly, the number of CCR4positive lymphocytes without atypical nuclei was 12 lymphocytes per 10 HPF (1.2 cell counts / HPF +-1.1). Theselymphocytes also increased to 26 lymphocytes per 7 HPF(3.7 cell counts / HPF +-5.0) (Fig. 2b-1, b-2 and c-1). Thesefindings may indicate that a reduction of normal Tregs wasinvolved in the recurrence of psoriasis vulgaris. On the other
hand, in the skin lesions from psoriasis vulgaris, FoxP3positive as well as CCR4-positive lymphocytes with atypical
nuclei, which corresponded to residual ATL cells, were substantially reduced to 13 lymphocytes per 7 HPF (1.9 cellcounts / HPF +-2.9) from 79 lymphocytes per 10 HPF (7.9cell counts / HPF +-4.1), and 9 lymphocytes per 7 HPF (1.3cell counts / HPF +-1.5) from 110 lymphocytes per 10 HPF(11.0 cell counts / HPF +-6.3), respectively (Fig. 2c-2).
CD4-positive
lymphocytes
alsodecreased(Fig. 2d-1 and d-2). These results indicated that mogamulizumab robustly suppressed the progression of ATL. Aftermogamulizumab therapy, the patient received hematopoietic
stem cell transplantation from a human leukocyte antigen(HLA)-identical sibling donor, which thus resulted in complete remission. The status of psoriasis vulgaris remained incomplete remission even after the hematopoietic stem celltransplantation.
Methods for immunofluorescent analyses of CCR4and FoxP3-positive lymphocytes in skin lesions
Biopsied samples from the skin lesion were subjected tohematoxylin-eosin staining and immunofluorescent analyses
for CCR4 (POTELIGEOⓇ test IHC, Kyowa Medex, Japan) (11) and FoxP3 (Perm Buffer Set. Cat No. 421403).
We counted the number of CCR4-positive, and FoxP3positive lymphocytes per 400× power fields in consecutive
sections.

Discussion
During the treatment of ATL, the case exemplified an expeditious emergence of systemic psoriasis vulgaris (Fig. 1).
At the time point of recurrence, the functional Tregs weremarkedly diminished as evidenced by FoxP3 and CCR4 immunohistochemistry analyses, raising the possibility thatmogamulizumab administration may have a considerable impact on the pathophysiology of systemic psoriasis vulgaris.
In the present case, erythematous skin lesions were consistent with psoriasis vulgaris in both the macroscopic and microscopic findings, where the dermatological involvement of
ATL cells was subtle (Fig. 2a-1 and b-1). Additionally, inthe dermatological inspection, the phenotype of the erythe-

mas largely differed from that in drug eruption. Although it
is occasionally hard to discriminate psoriasis vulgaris fromdrug eruption during the pathological examination,
eosinophil-poor drug eruptions observed in this case appeared to be unusual. This notion is reinforced by the factthat such erythemas completely disappeared during the treatment for psoriasis vulgaris. After five courses of mogamulizumab, the circulating level of mogamulizumab was presumed to be saturated, as assessed by the biological half-lifeof mogamulizumab (5). The time point was synchronizedwhen the skin lesions of psoriasis vulgaris were extended
systemically. In sharp contrast to the present erythema, theextension of the skin lesion in a previous episode of psoriasis vulgaris was localized only in the occipital area. All
these findings strongly suggest the causal relationship between the emergence of systemic psoriasis vulgaris and theadministration of mogamulizumab.
Psoriasis vulgaris is one of representative autoinflammatory diseases with an incidence of approximately 2% worldwide (14). In its pathogenesis, plasmacytoid dendritic cells(pDCs) are deeply involved, which play a critical role in responding to bacterial or viral DNA through Toll-like receptors, thereby producing interferon α, interferon β andinterleukin-6 (IL-6) (15). In patients with psoriasis vulgaris,an antimicrobial peptide, LL37, is expressed in the infection
sites and released from injured dermis or keratinocytes. Recent data suggest that LL37 activates pDCs and provokes
autoinflammation (16). IL-6 induces Th0 cell differentiation
into Th17 cells, which may also exacerbate psoriasis vulgaris (17). On the other hand, Tregs are known to eliminate
pathogenic T cells such as Th17 cells (18). Furthermore, arecent work suggests that the depletion of functional Tregs
might aggravate psoriasis vulgaris (19). Taken together, it isreasonable to speculate that mogamulizumab may have contributed to the recurrence of psoriasis vulgaris in this case.
It should be noted that CCR4 is expressed not only on thesurface of ATL cells, but also on normal lymphocytes including Tregs, monocytes and platelets (4). On the other
hand, FoxP3 is a master regulatory gene in the development
and function of Tregs (10). Importantly, the reduction of
FoxP3-positive lymphocytes is linked to the dysfunction ofTregs (11, 12). Following mogamulizumab treatment, FoxP
3-positive lymphocytes without atypical nuclei, which corresponded to normal Tregs in the skin lesions, were substantially decreased (Fig. 2a-1, a-2 and c-1), with a concomitantmarked reduction of CCR4-positive lymphocytes without
atypical nuclei (Fig. 2b-1, b-2 and c-1). These findings indicate that skin erythemas were caused by an autoinflammatory mechanism via the dysfunction of Tregs, rather thanskin invasion of residual ATL cells. In addition, this result
does not contradict the notion that Tregs are the origin of
ATL cells (3). In fact, previous studies (5, 13) have demonstrated the substantial reduction of functional Tregs by thetreatment of mogamulizumab. Furthermore, it is widely accepted that the balance between Tregs and Th17 cells is important for immunological homeostasis (20).

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Figure 2. Immunofluorescence analyses in the skin of the patient (400×). FoxP3 is a master regulatory gene for the function of Tregs. a-1, b-1) Both FoxP3-positive and CCR4-positive lymphocytes
were substantially decreased when psoriasis vulgaris emerged, 13 lymphocytes per 10 HPF and 12
lymphocytes per 10 HPF, respectively. a-2, b-2) In contrast, after psoriasis vulgaris improvement,
both FoxP3-positive and CCR4-positive lymphocytes without atypical nuclei were markedly increased (39 lymphocytes per 7 HPF and 26 lymphocytes per 7 HPF, respectively). Moreover, the immunoreactive intensity of CCR4-positive lymphocytes in b-2 was stronger than those in b-1. c-1) Agraphic demonstration of the cell counts per one HPF resulting from the immunofluorescence analyses. After the skin lesions of psoriasis vulgaris improved, FoxP3-positive lymphocytes without atypical nuclei increased approximately 4-fold and CCR4-positive lymphocytes without atypical nuclei
also increased approximately 3-fold. Consequently, normal Tregs showed a marked trend to decrease.
c-2) A graphic demonstration of the cell counts per one HPF as evidenced by the immunofluorescenceanalyses. FoxP3-positive lymphocytes with atypical nuclei were substantially reduced approximately
1/4-fold and CCR4-positive lymphocytes with atypical nuclei, which corresponded to residual ATL
cells, were also substantially reduced approximately 1/9-fold. d-1, d-2) CD4-positive lymphocytes also
decreased. These findings indicate that her skin erythemas were caused by the dysfunction of normal
Tregs, rather than skin invasion of residual ATL cells.

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Collectively, the present case may provide insight into themechanistic link between the dysfunction of Tregs andpathophysiology of recurrence of autoinflammatory diseases.
Written informed consent was obtained from the patient for
publication of this case report.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
We are grateful to Y. Kishimoto, M. Aoki, M. Hirata, I. Asato,
C. Noguchi, M.Shimoji and Y Kuniyoshi for their secretarial assistance.

References
1. Tsukasaki K, Utsunomiya A, Fukuda H, et al. VCAP-AMP-VECP
compared with biweekly CHOP for adult T-cell leukemialymphoma: Japan Clinical Oncology Group Study JCOG 9801. J
Clin Oncol 25: 5458-5464, 2007.
2. Hishizawa M, Kanda J, Utsunomiya A, et al. Transplantation ofallogeneic hematopoietic stem cells for adult T-cell leukemia: anationwide retrospective study. Blood 116: 1369-1376, 2010.
3. Yano H, Ishida T, Inagaki A, et al. Regulatory T-cell function of
adult T-cell leukemia/lymphoma cells. Int J Cancer 120: 20522057, 2007.
4. Yoshie O, Fujisawa R, Nakayama T, et al. Frequent expression of
CCR4 in adult T-cell leukemia and human T-cell leukemia virus
type 1-transformed T cells. Blood 99: 1505-1511, 2002.
5. Ishida T, Joh T, Uike N, et al. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemialymphoma: a multicenter phase II study. J Clin Oncol 30: 837842, 2012.
6. Ishida T, Ito A, Sato F, et al. Stevens-Johnson Syndrome associated with mogamulizumab treatment of adult T-cell leukemia /lymphoma. Cancer Sci 104: 647-650, 2013.
7. Ozen S, Bilginer Y. A clinical guide to autoinflammatory diseases:
familial Mediterranean fever and next-of-kin. Nat Rev Rheumatol
10: 135-147, 2014.
8. Kakeda M, Arock M, Schlapbach C, Yawalkar N. Increased ex-pression of heat shock protein 90 in keratinocytes and mast cells
in patients with psoriasis. J Am Acad Dermatol 70: 683-690,
2014.
9. Ishida T, Utsunomiya A, Iida S, et al. Clinical significance of
CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. Clin
Cancer Res 9: 3625-3634, 2003.
10. Zheng Y, Rudensky AY. FoxP3 in control of the regulatory T celllineage. Nat Immunol 8: 457-462, 2007.
11. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells
and immune tolerance. Cell 133: 775-787, 2008.
12. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing
IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155: 1151-1164, 1995.
13. Sugiyama D, Nishikawa H, Maeda Y, et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells,
evoking antitumor immune responses in humans. PNAS 110:
17945-17950, 2013.
14. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med 361:
496-509, 2009.
15. Jego G, Palucka AK, Blanck JP, Chalouni C, Pascual V,
Banchereau J. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity
19: 225-234, 2003.
16. Lande R, Gregorio J, Facchinetti V, et al. Plasmacytoid dendritic
cells sense self-DNA coupled with antimicrobial peptide. Nature
449: 564-569, 2007.
17. Di Cesare A, Di Meglio P, Nestle FO. The IL-23/Th17 axis in the
immunopathogenesis of psoriasis. J Invest Dermatol 129: 13391350, 2009.
18. Sugiyama H, Gyulai R, Toichi E, et al. Dysfunctional blood andtarget tissue CD4+ CD25 high regulatory T cells in psoriasis:mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol 174: 164-173, 2005.
19. Furuhashi T, Saito C, Torii K, et al. Photo(chemo)therapy reduces
circulating Th17 cells and restores circulating regulatory T cells in
psoriasis. PLoS ONE 8: e54895, 2013.
20. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature 441: 235-238, 2006.

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